Beyond Flexner 2016: Push for Change

Transcription

1 Beyond Flexner 2016: Push for Change African Ancestry and High-Risk/Triple Negative Breast Cancer: From Tuskegee and Race Medicine to Precision Medicine and Oncologic Anthropology Lisa A. Newman, MD, MPH, FACS, FASCO Henry Ford Health System Director, Breast Oncology Program Director, International Center for the Study of Breast Cancer Subtypes Adjunct Professor of Surgery, M.D. Anderson Cancer Center Adjunct Professor of Health Policy Management, UM SPH

2 I have no disclosures

3 Tuskegee Study and Race Medicine : Study of Untreated Syphilis in the Negro Male 1932: Study initiated 1943: Penicillin accepted as standard treatment, but withheld from study subjects 1972: Study details reported by news media 1973: Study discontinued Treatment instituted and all medical expenses paid for the rest of the subjects lives 1997: President Clinton formally apologizes to trial participants and their families on behalf of the U.S. government

4 SOCIOECONOMIC DISPARITIES 35% White American African American 33% 30% 27% Latino American 28% 25% 20% 24% 22% American Indian/Alaskan Native Asian American 19% 18% 15% 10% 8% 10% 11% 5% 0% Proportion with Poverty-Level Income Proportion with No Medical Insurance

5 Breast Cancer Burden of African Americans Higher mortality Advanced stage distribution Socioeconomic Disparities Tumor biology Lower lifetime incidence Younger age distribution Increased frequency of adverse tumor features Higher incidence of male breast cancer Genetics Lifestyle & Reproductive Experiences Environmental exposures Diet/Nutrition

6 SES-Adjusted Meta-Analysis, 2006 >13K AA & 75K WA Breast CA Pts; 19 Studies Bassett Coates Gordon Ansell Neale Eley Perkins Simon (>49 yo) Simon (<50 yo) Franzini Howard Wojcik Yood El Tamer Roetzheim Albain Premen Albain Postmen Polednak Bradley Jatoi Crowe Combined mortality hazard AA Mortality Risk: 1.28 (95% CI ) Newman et al, JCO 2006

7 Breast Cancer Burden of African Americans Higher mortality Advanced stage distribution Lower lifetime incidence Younger age distribution Increased frequency of adverse tumor features Higher incidence of male breast cancer Socioeconomic Disparities Delivery of Care Tumor biology Genetics Lifestyle & Reproductive Experiences Environmental exposures Diet/Nutrition

8 Disentangling SES and Inherent Racial/Ethnic Cancer Risks Clinical Trials Data Albain et al, JNCI 2009: Pooled analyses of SWOG adjuvant therapy trials Equal treatments delivered through clinical trials resulted in equal outcomes for all cancers (regardless of race/ethnicity) except for African Americans with hormonally-driven cancers (breast & prostate cancers) Recurrence Premenopausal 1.39 ( ) Postmenopausal 1.45 ( ) Mortality 1.41 ( ) 1.49 ( )

9 TIME.com Aug 22, 2009 Why Racial Profiling Persists in Medical Research By Catherine Elton

10 SEER Program: Breast Cancer Incidence and Mortality Rates, African Am erican Incidence White Am erican Incidence African Am erican Mortality White Am erican Mortality

11 SEER Program: Breast Cancer Incidence and Mortality Rates, African Am erican Incidence White Am erican Incidence African Am erican Mortality White Am erican Mortality Tamoxifen

12 Proportion ER-Negative Breast Cancer 45% 40% Disparities in Breast Tumor Biology: ER-Negative Breast Cancer in the U.S. 39% 35% 30% 25% 22% 32% 25% 31% 20% 15% 10% 5% 0% White American African American Li et al; SEER Data, Arch Int Med 2003 American Indian Asian/Pacific Islander Hispanic/Latina American

13 Microarray and Immunohistochemistry to Identify of Breast Tumor Subtypes Carolina Breast Cancer Study: Frequency of basal subtype by IHC 50% 40% 30% 20% 10% 0% 39% 26% 16% 16% 14% 16% AA All WA All AA Premen WA Postmen AA Postmen WA Postmen Copyright restrictions may apply. Carey, L. A. et al. JAMA 2006;295:

14 Dataset/Sample Size Frequency of TNBC Carey, premenopausal AA vs 164 premenopausal WA women; Carolina Breast Cancer Study Morris, 2007 AA WA P 39% 16% < Thomas Jefferson Univ Hosp pts; 197,274 SEER pts 20.8% 10.4% < Lund, 2008 Lund, 2008 Moran, 2008 Chavez- MacGregor 2013 Population-based Atlanta GA cohort of 116 AA, 360 WA pts 167 AA and 23 WA from Grady Hospital; Atlanta, GA 99 AA; 968 WA BCS pts from Yale Univ School of Medicine 606 cases of male breast cancer, population-based California Cancer Registry 46.6% 21.8% < % 13.0% % 8% < % 3% NR

15 Incidence Rate (per 100,000) Population-Based Incidence Rates of TNBC, by Race/Ethnicity and Age: Implications for Screening Recommendations White Black < Age (years) Delayed mammography screening may worsen breast CA outcome disparities between AA and WA women (Amrikia and Newman, CANCER, 2011)

16 Annual report to the nation on the status of cancer, , featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state TNBC WA TNBC AA TNBC Asian/PI TNBC Hispan Kohler B et al, April 2015

17 Breast cancer statistics, 2015: Convergence of incidence rates between black and white women Systemic therapy advances: Endocrine Tx Anti-HER2 therapy Mortality disparity Δ=42% CA: A Cancer Journal for Clinicians 29 OCT 2015

18 Precision Medicine Breast cancer precursors revisited: molecular features & progression pathways Prior benign breast biopsies and fibrocystic histopathology are risk factors for non-tnbc; Reis-Filho J et al; Histopathology 2010 What are the TNBC precursors?

19 HFHS Benign Breast Disease Cohort HFHS female patients Age years Prior cancer history excluded Minimum six months HFHS interaction/affiliation 2,588 African Americans 3,566 White Americans

20 Variable African- Americans N= 2,588 (%) White- Americans N=3,566 (%) P-Value 95% CI Mean age at diagnosis of BBD (± SD) 51.7 (± 8.3) 52.1 (±8.4) Method of BBC Detection Asymptomatic/Screening Mammogram Clinical Breast Examination Symptomatic Pain and Tenderness Lump Clear Discharge Bloody Discharge Extent of BBC Treatment Excision/Lumpectomy Biopsy (Needle/Core) Histology of Benign Lesions Non-Proliferative Hyperplasia with Atypia Ductal Lobular Ductal and Lobular Lobular Carcinoma In Situ 2,019 (78.4) 48 (1.9) 89 (3.5) 310 (12.0) 51 (2.0) 33 (1.3) 376 (14.7) 2,216 (83.3) 2,438 (94.2) 122 (4.7) 19 (0.7) 6 (0.2) 3 (0.1) 2,799 (78.9) 126 (3.5) 94 (2.6) 436 (12.3) 53 (1.5) 20 (0.6) 583 (16.5) 2,799 (79.4) 3,283 (92.0) 207 (5.8) 52 (1.5) 21 (0.6) 3 (0.1)

21 Henry Ford Health System Benign Breast Disease Cohort: TNBC Incidence White/Caucasian Americans African Americans

22 High-Risk Breast Cancer and African Ancestry Parallels between hereditary breast cancer and breast cancer in women with African ancestry younger age distribution increased prevalence of ER-neg, aneuploid tumors higher risk of male breast cancer Is African ancestry associated with a heritable marker for highrisk breast cancer subtypes? Unique opportunity to gain insights regarding etiology of breast cancer disparities and the pathogenesis of triple-negative breast cancer

23 International Breast Cancer Research Collaborative Overarching Goal: To evaluate association between African ancestry & high-risk breast cancer subtypes Characterizing the breast cancer burden of Sub- Saharan Western Africa Komfo Anoyke Teaching Hospital, Kumasi Ghana

24 Michigan-Ghana Breast Cancer Research Collaborative Overarching Goal: To evaluate association between African ancestry & high-risk breast cancer subtypes Comparison of WA, AA, and Ghanaian pts Henry Ford Hospital, Detroit; KATH, Ghana WA N=321 AA N=272 Ghana N=234 PValue Average Age TNBC 16% 26% 53% <0.001

25 Korle Bu Teaching Hospital 2010 Accra, Ghana 2% Molecular Marker Pattern 2% 2% 1% ER neg/pr neg/her2 neg (TNBC) 4% ER neg/pr neg/her2 pos 5% ER pos/pr neg/her2 neg 26% 58% ER neg/pr pos/her2 neg ER neg/pr pos/her2 pos ER pos/pr pos/her2 neg ER pos/pr pos/her2 pos N=219 ER pos/pr neg/her2 pos Der and Newman, The Breast J, 2015

26 TNBC: International Patterns USA; Europe: 10-20% of all invasive cancers Canada: 11% Dent et al, Clin Cancer Res, 2007 Turkey: 12% Turkoz et al, The Breast, 2013 Greece: 8% Fostira et al, Br Cancer Res Tr, 2012 China: 22% Song et al, PLoS One, 2013

27 ALDH-1 Staining by Race/Ethnicity (Newman et al Cancer, 2012) 80% 70% 60% 50% 40% 30% 20% 10% 0% Ghanaian CA HFH AA CA HFH WA CA French/Eur CA UM WA CA Consistent with results in Uganda breast cancer pts (Nalwoga et al, Br J Cancer 2010) 69 benign Ghanaian breast specimens studied at UM 58% ALDH1-positive

28 African Ancestry and TNBC Heterogeneity: Xenograft Creation - NOD/SCID mice humanized at UM with fibroblasts from reduction mammoplasty cases prior to travel De novo creation of lab at KATH for preparation of tumor specimens procured directly from OR Implantation into mice mammary fat pads immediately upon return to UM

29 African Ancestry and TNBC Heterogeneity: TNBC Subtypes Vanderbilt University (Pietenpol; Lehmann) Gene expression profiles; 21 breast CA datasets >3,000 cases, including 587 TNBC (18% TNBC) Geographic sources: US (predominately Caucasian cases); UK; Sweden; Germany; Singapore; Netherlands 6 subtypes; varying degrees of stem cell-like versus Luminal Androgen Receptor (LAR)-like properties Treatment response/predictive value of TNBC subtype MD Anderson TNBC subtype associated with response to neoadjctx LAR subtype with lowest response Therapeutic implications bicalutamide/anti-androgen therapy in LAR subtype

30 Associations with AR level among TNBC samples (n=80) AR Level p-value ALDH1 Negative 38 (86.4) 6 (13.6) ALDH1 Positive 23 (63.9) 13 (36.1) ) Androgen Receptor positivity associated with ALDH1 expression: Novel, as-yet undefined additional TNBC subtype featuring joint expression of AR and ALDH-1??? Proctor and Newman, Ann Surg Onc, 2015

31 Ultimate Goal: Eliminating the Threat of Breast Cancer Worldwide International Collaborations: Opportunities to study disparities in high-risk patterns of disease Opportunities to improve the standard of health care in medically-underserved populations Opportunities to cultural and academic exchange Opportunities to forge powerful friendships

32 Breast Cancer in Ghana

33 KATH Surgical Suite

34 Michigan-Ghana Collaboration: Academic Exchange Growth and Evolution of Weekly KATH Multidisciplinary Breast CA Tumor Board/Teleconference

35 Michigan-Ghana Collaboration: Investment in Ghana Community Donation of medical supplies and educational materials to KATH hospital school

36 Michigan-Ghana Collaboration: Investment in Ghanaian Healthcare Resources, supplies, and support for KATH Breast Clinic staff Establishment of KATH dedicated breast clinicopathology team

37 Michigan-Ghana Collaboration: Academic Exchange Establishment of Immunohistochemistry Program at KATH Core Needle Biopsy Training Program (AnnSurgOnc 2010)

38 Expansion of International Registry: Addis Ababa, Ethiopia

39 Results: Phenotype Distribution 80% 70% P % White American Ghanaian African American Ethiopian 60% 50% P < % 40% 30% 20% 19.8% 37.1% 28.7% P = % 29.8% 20.1% 18.7% 16.7% 15.5% 15.0% 10% 0% ER-negative HER2-positive TNBC

40 Biologic Plausibility: African Diaspora/ Patterns of Forced Population Migration GHANA ETHIOPIA

41 Breast cancer is a heterogeneous disease Subtypes vary in treatment needs and prognosis Subtypes vary in genetic risk Subtypes vary in prevalence within population subsets Eliminating breast cancer is dependent upon our ability to understand and define its diverse nature Obligation to study to diverse populations worldwide Oncologic Anthropology ICS BCS Mission Statement: To reduce the global breast cancer burden through advances in research and delivery of care to diverse populations worldwide

42

43

44 SURVIVAL RATES 60% 43% 20%

45 R.M.S. TITANIC Passenger Status 1 st Class 2 nd Class 3 rd Class Survival Rate 60% 43% 20% Outcome is dependent on access to care Of all the forms of injustice, inequality in health care is the most shocking and inhumane Rev. Dr. Martin Luther King, Jr.

46 No quality without access American College of Surgeons, National Institute of Minority Health and Disparities, and American Cancer Society Collaborate to address unequal healthcare May, 2015 Bethesda, MD

47 THANK YOU!!!!!!

48 Acknowledgements Colleagues in Ghana: Dr. Baffour Awuah Dr. Joseph Oppong Dr. Frances Aitpillah Dr. Ishmael Kyei Dr. Francis Abantaga Dr. Ernest Adjei Dr. Ernest Osei-Bonsu Dr. Michael Ohene-Yeboah Dr. Emmanuel Amankwaa-Frempong Patients of the Komfo Anokye Teaching Hospital Dr. Kofi Gyan Dr. Jessica Bensenhaver Dr. Erica Proctor Dr. David Nathanson Dr. Dhanitale Chitale Barbara Salem Dr. Azadeh Stark Colleagues in Ethiopia: Dr. Aisha Suleiman-Jibril Dr. Abebe Engida Dr. Bekele Mahteme Dr. Abebe Zerihun Patients of the St. Paul s Millenium Teaching Hospital Dr. Evelyn Jiagge Dr. Max Wicha Dr. Celina Kleer Dr. Sofia Merajver Kathy Toy Dr. Mark Hoenerhoff